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1.  The Timing Hypothesis: A Paradigm Shift in the Primary Prevention of Coronary Heart Disease in Women: Part 1, Comparison of Therapeutic Efficacy 
The long-held belief that outcome data from intervention trials in men are generalizable to women has created the framework in which the primary prevention of coronary heart disease (CHD) in women is viewed. However, over the past decade, data has accumulated to refute such a supposition of generalizability. These lines of evidence concern the sex-specific efficacy of CHD primary prevention therapies and timing of postmenopausal hormone replacement therapy (HRT) initiation according to age and/or time-since-menopause as modifiers of efficacy and risk. Although the standard primary prevention therapies of statins and aspirin reduce CHD in men, neither therapy reduce CHD, and more importantly total mortality in women under primary prevention conditions. On the other hand, HRT significantly reduces both CHD and total mortality in primary prevention when HRT is initiated in women <60 years old and/or <10 years-since-menopause. Herein, the efficacy of the commonly used therapies for the primary prevention of CHD in women, statins, aspirin and postmenopausal HRT is discussed. In part 2 of this series the comparative risks of these therapies are discussed.
doi:10.1111/jgs.12140
PMCID: PMC3660423  PMID: 23414520
hormone therapy in women; statins; timing hypothesis; women and CHD prevention; 31 meta-analyses
2.  Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS–Cognitive and Affective Study 
PLoS Medicine  2015;12(6):e1001833.
Background
Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.
Methods and Findings
KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes.
On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y.
Conclusions
The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles.
Trial Registration
ClinicalTrials.gov NCT00154180 and NCT00623311
In a randomized, controlled trial, Carey Gleason and colleagues examine the effects of hormone therapies on cognitive and mood outcomes in recently postmenopausal women.
Editors' Summary
Background
Menopause (“change of life”)—the time in a woman’s life when her menstrual periods stop—is a normal part of aging and usually occurs around the age of 50. In the years before menopause (the menopausal transition or perimenopause), the levels of estrogen and progesterone—sex hormones produced by the ovaries that prepare the woman’s body every month for a possible pregnancy—go up and down irregularly. This variation in hormone levels changes the frequency and characteristics of a woman’s periods but can also cause hot flashes (feeling hot on and off during the day), night sweats, vaginal dryness, bone thinning, and mood swings. Some women sail through menopause without experiencing any of these symptoms, but for other women menopausal symptoms, which can continue for several years after menopause, can be debilitating. For these women, menopausal hormone therapy (MHT, previously known as hormone replacement therapy, or HRT)—treatment with various combinations and types of estrogen and progesterone—can be prescribed during or after the menopausal transition to manage their troublesome symptoms.
Why Was This Study Done?
Although MHT has helped many women deal with their menopausal symptoms, it can increase a woman’s risk of heart disease, stroke, blood clots, and breast cancer. There is also some evidence that MHT increases the risk of cognitive decline (decline in thinking, language, memory, understanding, and judgment) and dementia in women who start taking MHT after the age of 65. However, other evidence suggests that MHT might enhance cognition and mood if it is given at menopause rather than later. In this randomized, double-blinded, placebo-controlled clinical trial (the KEEPS-Cog trial, an ancillary study of the Kronos Early Estrogen Prevention Study, which examined the effect of MHT on cardiovascular health), the researchers investigate the effects of up to four years of MHT on cognition and mood in recently postmenopausal women living in the US. A randomized, placebo-controlled clinical trial compares the outcomes of participants assigned an active intervention or a placebo (dummy) intervention through the play of chance; in a double-blinded trial, neither the researchers nor the participants know who is receiving which treatment until the trial ends.
What Did the Researchers Do and Find?
In the KEEPS-Cog trial, 220 healthy recently postmenopausal women took an estrogen pill every day and a progesterone pill for the first 12 days of each month, 211 women wore an estradiol patch (transdermal estradiol) and took a progesterone pill for the first 12 days of each month, and 262 women received placebo patches and pills for up to four years (the average follow-up was a little less than three years). The researchers assessed the trial participants for their overall cognitive health using an instrument called the Modified Mini-Mental State Examination, for four specific cognitive functions using several established instruments, for depression symptoms using the Beck Depression Inventory, and for mood using the Profile of Mood States instrument at baseline and at 18, 36, and 48 months. Statistical analysis of the data collected indicates that, during the trial, there were no treatment-related effects on cognition or depression symptoms. However, women treated with estrogen pills and progesterone (but not those treated with estradiol patches and progesterone) showed improvements in some mood symptoms compared to women in the placebo group.
What Do These Findings Mean?
Before starting their trial, the researchers hypothesized that, because the body handles different formulations and types of estrogen in different ways, transdermal estradiol but not oral estrogen would improve cognition and mood in recently postmenopausal women when compared to placebo. Notably, the findings suggest that MHT does not alter cognition as hypothesized and that oral rather than transdermal estrogen has a small to moderate beneficial effect on mood. Importantly, these findings provide no information about the effects of MHT beyond four years and, because most of the women in the study were white, well-educated, and at low risk of cardiovascular disease, may not be applicable to the general postmenopausal population of the US and of other countries. Moreover, because MHT improved menopausal symptoms in the women receiving hormones, the trial was not truly double-blinded. However, despite these and other study limitations, the researchers suggest that their findings could now be used to help women make more informed decisions about whether to use MHT to manage their menopausal symptoms.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001833.
The US National Institute on Aging provides detailed information for women about menopause (in English and Spanish) and about hormones and menopause
The UK National Health Service Choices website also provides detailed information about menopause and about menopausal hormone therapy, including some personal stories
The US Food and Drug Administration provides answers to common questions about menopause and hormones (in English and Spanish)
MedlinePlus provides links to further resources and advice about menopause and about menopausal hormone therapy (in English and Spanish)
More information about the KEEPS-Cog trial is available
doi:10.1371/journal.pmed.1001833
PMCID: PMC4452757  PMID: 26035291
3.  Isoflavone Soy Protein Supplementation and Atherosclerosis Progression in Healthy Postmenopausal Women: A Randomized Controlled Trial 
Background and Purpose
Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective, use of isoflavone soy protein (ISP) supplementation as a primary preventive therapy remains unexplored. We determined whether ISP reduces subclinical atherosclerosis assessed as carotid artery intima-media thickness (CIMT) progression.
Methods
In a double-blind, placebo-controlled trial, 350 postmenopausal women 45–92 years of age without diabetes and cardiovascular disease (CVD) were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7-years.
Results
Overall, mean (95% confidence interval) CIMT progression rate was 4.77(3.39–6.16) μm/year in the ISP group and 5.68(4.30–7.06) μm/year in the placebo group. Although CIMT progression was reduced on average by 16% in the ISP group relative to the placebo group, this treatment effect was not statistically significant (p=0.36). Among the subgroup of women who were randomized within 5 years of menopause, ISP participants had on average a 68% lower CIMT progression rate than placebo participants 2.16(−1.10–5.43) vs. 6.79(3.56–10.01) μm/year, p=0.05). ISP supplementation had a null effect on women who were >5 years beyond menopause when randomized. There were no major adverse events from ISP supplementation.
Conclusion
ISP supplementation did not significantly reduce subclinical atherosclerosis progression in postmenopausal women. Subgroup analysis suggest that ISP supplementation may reduce subclinical atherosclerosis in healthy young (median age, 53 years) women at low-risk for CVD who were <5 years postmenopausal. These first trial results of their kind warrant further investigation.
doi:10.1161/STROKEAHA.111.620831
PMCID: PMC3202054  PMID: 21903957
Atherosclerosis; Cardiovascular disease; Intima-media thickness; Isoflavones; Menopause; Soy; Women
4.  NOS1 Methylation and Carotid Artery Intima Media Thickness in Children 
Background
Nitric oxide (NO) plays an important role in cardiovascular health by maintaining and regulating vascular tone and blood flow. Epigenetic regulation of nitric oxide synthase (NOS), the genes responsible for NO production, may affect cardiovascular disease including development of atherosclerosis in children.
Methods and Results
We measured percentage DNA methylation using bisulfite conversion and Pyrosequencing assays on DNA from buccal cells provided by 377 participants of the Children’s Health Study on whom carotid artery intima-media thickness (CIMT) measurements were also collected. We examined a total of 16 CpG loci located within NOS1, NOS2A, NOS3, ARG1 and ARG, genes responsible for NO production. CIMT was measured using high-resolution B-mode carotid ultrasound. The association between percentage DNA methylation in ARG and NOS genes with CIMT was evaluated using linear regression adjusted for sex, Cethnicity, body mass index, age at CIMT, town of residence and experimental plate for pyrosequencing reactions. Differences in the association by ethnicity and ancestral group were also evaluated. For a 1% increase in average DNA methylation of NOS1, CIMT increased by 1.2 μm (p=0.02). This association was greater in Hispanic children of Native American descent (β = 2.3, p=0.004) than in Non-Hispanic Whites (β = 0.3, p=0.71) or Hispanic Whites (β = 1.0, p=0.35).
Conclusions
DNA methylation of NOS1 has a plausible role in atherogenesis through regulation of NO production, though ancestry may alter the magnitude of this association.
doi:10.1161/CIRCGENETICS.113.000320
PMCID: PMC4008829  PMID: 24622112
epigenetics; intima-media thickness; cardiovascular disease; nitric oxide synthase
5.  The Effect of Prior Oophorectomy on Changes in Bone Mineral Density and Carotid Artery Intima-Media Thickness in Postmenopausal Women 
Fertility and sterility  2014;101(4):1117-1122.
Objective
To determine the effect of prior oophorectomy in healthy postmenopausal women on the rate of loss of bone mineral density (BMD) and rate of increase in carotid artery intima-media thickness (CIMT)
Design
Secondary analysis from a randomized controlled trial
Setting
University-based research clinic
Patient(s)
222 healthy postmenopausal women in the Greater Los Angeles Area
Intervention(s)
Baseline and annual screening of BMD and assessment of CIMT every 6 months for a total of 3 years
Main Outcome and Measure(s)
Changes in BMD and CIMT during postmenopausal years
Result(s)
Among women who were menopausal more than 10 years, the rate of CIMT progression was statistically significantly less in women with intact ovaries compared to prior oophorectomy. In women 5-10 years postmenopausal, there was a trend toward a slower loss of BMD in those who retained their ovaries and in women more than 10 years menopausal there was significantly less BMD loss in those who retained their ovaries.
Conclusion(s)
As time from menopausal transition increases, retained ovaries are associated with a slower rate of bone loss and a slower rate of thickening of the carotid artery wall compared to rates in menopausal women with oophorectomy.
doi:10.1016/j.fertnstert.2013.12.055
PMCID: PMC4215065  PMID: 24530156
menopause; oophorectomy; bone mineral density; intima-media thickness
6.  Associations of Urine Excretion of Isoflavonoids with Cognition in Postmenopausal Women in the Women’s Isoflavone Soy Health Clinical Trial 
Background/Objectives
Results from randomized trials of soy supplements on cognition in postmenopausal women are equivocal. We sought to determine associations of change in urine excretion of isoflavonoids on cognitive change.
Design
Post hoc analysis of isoflavonoid exposures (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women’s Isoflavone Soy Health trial.
Setting
General community.
Participants
350 healthy postmenopausal women.
Intervention
25 g of isoflavone-rich soy protein (91 mg of aglycone weight isoflavones: 52 mg genistein, 36 mg daidzein, 3 mg glycitein) or milk protein-matched placebo, provided daily.
Measurements
Overnight urine excretion and fasting plasma levels of isoflavonoids, and cognitive function, measured at baseline and endpoint.
Results
300 women (mean age = 61 years, range 45-92 years) completed both cognitive assessments and did not use hormone replacement therapy during the trial. Mean on-trial change from baseline in urine excretion of isoflavonoids was not significantly associated with change in a composite score of global cognition (p=0.39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (p=0.02), but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score among women in the first compared to highest quartile of isoflavonoid change are equivalent to an approximate 4.4 year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results.
Conclusion
Among healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results. Increasing isoflavonoid exposure from dietary supplements is, however, associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.
doi:10.1111/jgs.12752
PMCID: PMC4226524  PMID: 24617349
Cognition; isoflavones; menopause; soy; women’s health
7.  Immunologic Predictors of Coronary Artery Calcium Progression in a Contemporary HIV Cohort 
AIDS (London, England)  2014;28(6):831-840.
Background
Identifying immunologic mechanisms that contribute to premature cardiovascular disease (CVD) among HIV-positive patients will inform prevention strategies.
Methods
Coronary artery calcium (CAC) progression was studied in an HIV cohort. Immunophenotypes were measured on baseline cryopreserved peripheral blood mononuclear cells using multi-color flow cytometry. Logistic regression identified predictors of CAC progression after adjusting for traditional and HIV -related risk factors.
Results
Baseline characteristics for the analysis cohort (n=436) were: median age 42 years, median CD4 count 481cells/mm3, and 78% receiving ART. Higher frequencies of CD16+ monocytes were associated with greater likelihood of CAC progression, after adjusting for traditional and HIV risk factors (OR per doubling was 1.66 for CD14+/CD16+ [p=0.02], 1.36 for CD14dim/CD16+ [p=0.06], and 1.69 for CD14var/CD16+ [p=0.01]). Associations for CD16+ monocytes persisted when restricted to participants with viral suppression. We found no significant associations for CAC progression with other cellular phenotypes, including T-cell activation and senescence markers.
Conclusions
Circulating CD16+ monocytes, potentially reflecting a more pro-atherogenic subpopulation, independently predicted greater CAC progression among HIV-infected persons at low risk for AIDS. In contrast to T-cell abnormalities classically associated with AIDS-related disease progression, these data highlight the potential role of monocyte activation in HIV-related CVD risk.
doi:10.1097/QAD.0000000000000145
PMCID: PMC4199584  PMID: 24370480
HIV; cardiovascular disease; coronary artery calcium; immune activation; monocyte activation; inflammation
8.  The KEEPS-Cognitive and Affective Study: Baseline Associations between Vascular Risk Factors and Cognition 
Background
Midlife vascular risk factors influence later cognitive decline and Alzheimer’s disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contribute to cognitive dysfunction and AD.
Methods
We describe the extent to which vascular risk factors relate to cognition in healthy, middle–aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group design, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition.
Results
The KEEPS-Cog cohort (N=662) is healthy and free of cognitive dysfunction. Higher systolic BP was related to poorer performance in auditory working memory and attention (unadjusted p=0.004; adjusted p=0.10). This relationship was not associated with endogenous hormone levels.
Conclusions
Lower BP early in menopause may positively affect cognitive domains known to be associated with AD.
doi:10.3233/JAD-130245
PMCID: PMC4367860  PMID: 24430001
Clinical Trial; Estrogen; Blood Pressure; Vascular Risk; Hormone Therapy; Estradiol; Cognition; Attention; Memory
9.  Predictors of Subclinical Atherosclerosis in Women With Spinal Cord Injury 
Background:
Chronic spinal cord injury (SCI) is associated with an increase in risk factors for cardiovascular disease (CVD). In the general population, atherosclerosis in women occurs later than in men and usually presents differently. Associations between risk factors and incidence of CVD have not been studied in women with SCI.
Objective:
To determine which risk factors for CVD are associated with increased carotid intima-media thickness (CIMT), a common indicator of atherosclerosis, in women with SCI.
Methods:
One hundred and twenty-two females older than 18 years with traumatic SCI at least 2 years prior to entering the study were evaluated. Participants were asymptomatic and without evidence of CVD. Exclusion criteria were acute illness, overt heart disease, diabetes, and treatment with cardiac drugs, lipid-lowering medication, or antidiabetic agents. Measures for all participants were age, race, smoking status, level and completeness of injury, duration of injury, body mass index, serum lipids, fasting glucose, hemoglobin A1c, and ultrasonographic measurements of CIMT. Hierarchical multiple linear regression was conducted to predict CIMT from demographic and physiologic variables.
Results:
Several variables were significantly correlated with CIMT during univariate analyses, including glucose, hemoglobin A1c, age, and race/ethnicity; but only age was significant in the hierarchical regression analysis.
Conclusions:
Our data indicate the importance of CVD in women with SCI.
doi:10.1310/sci2002-90
PMCID: PMC4252167  PMID: 25477730
age; cardiovascular disease; carotid intima-media thickness; hemoglobin A1c; risk factors; smoking
10.  Echolucency of the Carotid Artery Intima‐Media Complex and Intima‐Media Thickness Have Different Cardiovascular Risk Factor Relationships: The Women's Interagency HIV Study 
Background
Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging.
Methods and Results
We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group.
Conclusions
Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.
doi:10.1161/JAHA.114.001405
PMCID: PMC4345869  PMID: 25699995
carotid arteries; epidemiology; immune system; risk factors; ultrasonics
11.  Reduced CD14 expression on classical monocytes and vascular endothelial adhesion markers independently associate with carotid artery intima media thickness in chronically HIV-1 infected adults on virologically suppressive anti-retroviral therapy 
Atherosclerosis  2013;232(1):52-58.
HIV infection causes systemic immune inflammation, and increases the risk for cardiovascular (CVD) disease even among those on virologically suppressive anti-retroviral treatment (ART). We performed a biostatistical analysis and screen of candidate cellular and plasma biomarkers for association with carotid artery intima-media thickness (CIMT), independent of traditional CVD risk factors such as age, gender, systolic blood pressure (SBP), lipid levels, smoking and diabetes. We conducted a multi-stage analysis based on a cross-sectional study of CVD risk in HIV-infected subjects age >45 years on ART for >6 months. The goal of this analysis was to identify candidate cellular and plasma biomarkers of CIMT in HIV-1 infected adults. We further sought to determine if these candidate biomarkers were independent of traditional CVD risk factors previously identified in HIV negative adults. High-resolution B-mode ultrasound images of the right common carotid common artery (CCA) were obtained. Plasma soluble inflammatory mediators, cytokines and chemokines were detected. Monocytes were defined by CD14/CD16 expression, and CD8+ T-cell activation by CD38/HLA-DR expression. Subjects were a median of 49.5 years old, 87% male, had a CIMT of 0.73 mm, FRS of 6%, a median viral load of 48 copies/mL, and CD4+ T cell count of 479 cells/μL. Soluble VCAM-1, and expansion of CD14dimCD16− monocytes each associated with higher CIMT independently of age and SBP. These factors are distinct components of a shared atherogenic process; 1) vascular endothelial molecular expression and 2) vascular monocytes that enter into the vascular endothelium and promote atherosclerotic plaque.
doi:10.1016/j.atherosclerosis.2013.10.021
PMCID: PMC3919042  PMID: 24401216
HIV; Carotid intima-media; CIMT; Cardiovascular disease; Framingham risk score; Biomarker; Screen; Regression; CD14; Monocytes; VCAM-1; Cytokines
12.  Components of Air Pollution and Cognitive Function in Middle-aged and Older Adults in Los Angeles 
Neurotoxicology  2013;40:1-7.
While experiments in animals demonstrate neurotoxic effects of particulate matter (PM) and ozone (O3), epidemiologic evidence is sparse regarding the relationship between different constituencies of air pollution mixtures and cognitive function in adults. We examined cross-sectional associations between various ambient air pollutants [O3, PM2.5 and nitrogen dioxide (NO2)] and six measures of cognitive function and global cognition among healthy, cognitively intact individuals (n=1,496, mean age 60.5 years) residing in the Los Angeles Basin. Air pollution exposures were assigned to each residential address in 2000–06 using a geographic information system that included monitoring data. A neuropsychological battery was used to assess cognitive function; a principal components analysis defined six domain-specific functions and a measure of global cognitive function was created. Regression models estimated effects of air pollutants on cognitive function, adjusting for age, gender, race, education, income, study and mood. Increasing exposure to PM2.5 was associated with lower verbal learning (β = −0.32 per 10 ug/m3 PM2.5, 95% CI = −0.63, 0.00; p = 0.05). Ambient exposure to NO2 >20 ppb tended to be associated with lower logical memory. Compared to the lowest level of exposure to ambient O3, exposure above 49 ppb was associated with lower executive function. Including carotid artery intima-media thickness, a measure of subclinical atherosclerosis, in models as a possible mediator did not attenuate effect estimates. This study provides support for cross-sectional associations between increasing levels of ambient O3, PM2.5 and NO2 and measures of domain-specific cognitive abilities.
doi:10.1016/j.neuro.2013.09.004
PMCID: PMC3946571  PMID: 24148924
air pollution; cognitive dysfunction; dementia; particulate matter; ozone; verbal learning
13.  High-Dose B-Vitamin Supplementation and Progression of Subclinical Atherosclerosis: A Randomized Controlled Trial 
Background and Purpose
Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease (CVD), it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B-vitamin supplementation reduces subclinical atherosclerosis progression.
Methods
In this double-blind clinical trial, 506 participants 40–89 years of age with an initial tHcy >8.5 μmol/L without diabetes and CVD were randomized to high-dose B-vitamin supplementation (folic acid 5 mg + vitamin B12 0.4 mg + vitamin B6 50 mg) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima-media thickness (primary outcome) and multidetector spiral computed tomography to measure aortic and coronary artery calcium (secondary outcome).
Results
Although the overall carotid artery intima-media thickness progression rate was lower with B-vitamin supplementation than with placebo, statistically significant between-group differences were not found (p=0.31). However, among subjects with baseline tHcy≥9.1 μmol/L, those randomized to B-vitamin supplementation had a statistically significant lower average rate of carotid artery intima-media thickness progression compared with placebo (p=0.02); among subjects with a baseline tHcy <9.1 μmol/L there was no significant treatment effect (p-value for treatment interaction=0.02). B-vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups.
Conclusion
High-dose B-vitamin supplementation significantly reduces progression of early stage subclinical atherosclerosis (carotid artery intima-media thickness) in well-nourished healthy B-vitamin “replete” individuals at low-risk for CVD with a fasting tHcy >9.1 μmol/L.
doi:10.1161/STROKEAHA.108.526798
PMCID: PMC2701290  PMID: 19118243
Atherosclerosis; Computed tomography; Folate; Homocysteine; Intima-media thickness; Randomized controlled trials; Vitamin B12
14.  Blunted Nocturnal Cortisol Rise is Associated With Higher Carotid Artery Intima-Media Thickness (CIMT) in Overweight African American and Latino Youth 
Psychoneuroendocrinology  2013;38(9):1658-1667.
Background
Blunted diurnal cortisol variation has been associated with overt cardiovascular disease in adults. The relationship between the diurnal cortisol variation and subclinical atherosclerosis in youth has yet to be investigated. The objectives of this study were to: 1) determine the relationship between overnight cortisol measures and CIMT in overweight and obese, African-American and Latino children; 2) assess ethnic differences in these relationships and 3) explore whether overnight cortisol and CIMT relationships were independent of inflammatory markers, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).
Methods
One hundred and fifty-six overweight and obese African-American and Latino children (ages 8–17, 86M/70F, 55 African-American /101 Latino) underwent measures of CIMT by B-mode ultrasound, nocturnal cortisol rise (NCR=salivary cortisol rise from 2200hrs to awakening at 0530hrs), cortisol awakening response (CAR=salivary cortisol from time of awakening to 30 min later), fasting serum cortisol and overnight urinary free cortisol.
Results
Using linear regression, salivary cortisol0530hrs and NCR were negatively associated with CIMT (βstandardized = −0.215 and −0.220, p<0.01) independent of age, height, percent body fat, ethnicity and systolic blood pressure. Nocturnal salivary cortisol2200hrs, morning serum cortisol, and overnight urinary free cortisol were not associated with CIMT. Using ANCOVA, participants with LOW NCR (NCR <0.44µg/dL, n=52) had significantly greater CIMT than those with HIGH NCR (NCR ≥0.91 µg/dL, n=52; 0.632±0.008 vs. 0.603±0.008mm p=0.01) after controlling for covariates. Ethnicity was independently associated with CIMT, whereby African-American children had greater CIMT than Latino children (−0.028±0.009, p=0.006). The relationships between cortisol measures and CIMT did not differ between the two ethnic groups (all pinteraction=0.28–0.97). CRP, IL-6 and TNF-α were not associated with CIMT (p>0.05). IL-6 was inversely related to NCR (r=−0.186, p=0.03), but it did not explain the relationship between NCR and CIMT.
Conclusions
Salivary cortisol0530hrs and NCR, but not CAR, nocturnal salivary cortisol 2200hrs, morning serum cortisol or overnight urinary free cortisol, were associated with CIMT, independent of relevant covariates, including inflammatory factors. A low awakening salivary cortisol or a blunted NCR may be related to increased atherosclerosis risk in overweight and obese minority youth. These findings support adult studies suggesting flattened daytime diurnal cortisol variation impacts cardiovascular disease risk.
doi:10.1016/j.psyneuen.2013.01.011
PMCID: PMC3722251  PMID: 23433749
Obesity; cardiovascular risk; carotid artery; intima media thickness; cortisol
15.  THE EFFECT OF ISOFLAVONE SOY PROTEIN SUPPLEMENTATION ON ENDOMETRIAL THICKNESS, HYPERPLASIA AND ENDOMETRIAL CANCER RISK IN POSTMENOPAUSAL WOMEN: A RANDOMIZED CONTROLLED TRIAL 
Menopause (New York, N.Y.)  2013;20(8):840-844.
Objective
To determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women.
Methods
In this randomized, double-blind, placebo-controlled trial, 350 postmenopausal women 45–92 years of age were randomized to a total daily dose of 154 mg of ISP or a milk protein matched placebo for a 3-year period. Women with a surgically absent uterus were excluded from the analysis (final study population: n=224). The main outcome measures were the mean change in endometrial thickness on transvaginal ultrasound from baseline until up to 36 months of follow-up; the incidence of endometrial sampling, endometrial hyperplasia and endometrial cancer.
Results
A total of 666 visits among 224 participants were evaluated. Treatment groups did not significantly differ on the mean baseline or on-trial changes in endometrial thickness. Of the 103 placebo-treated participants, 7 (6.8%) underwent an endometrial biopsy; 6 (85.7%) of these biopsies were benign. One woman in the placebo group was diagnosed with complex endometrial hyperplasia with atypia and underwent a hysterectomy. The pathology result from this surgery was Stage IB endometrial cancer. Of the 121 participants in the soy group, 9 (7.4%) underwent an endometrial biopsy. The results were benign in all 9 cases (100%). Although the rate of hyperplasia / malignancy was higher in the placebo group (14.3% versus 0%), the difference was not statistically significant.
Conclusion
Three-year isoflavone soy protein (ISP) supplementation has no effect on endometrial thickness or rates of endometrial hyperplasia and cancer in postmenopausal women.
LEVEL OF EVIDENCE
I
doi:10.1097/GME.0b013e3182804353
PMCID: PMC3934100  PMID: 23422867
Isoflavones; menopause; endometrium; randomized controlled trial
17.  Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV Study 
AIDS (London, England)  2013;27(9):1516-1519.
Summary
Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.
doi:10.1097/QAD.0b013e32835fd8a9
PMCID: PMC3909663  PMID: 23435295
lipids; HAART; HIV infection; inflammation
18.  Birth Weight and Carotid Artery Intima-Media Thickness 
The Journal of pediatrics  2012;162(5):906-11.e1-2.
Objectives
To determine the association between birth weight and carotid artery intima-media thickness (CIMT), a measure of atherogenesis, in a population of 11-year-old children.
Study design
CIMT measured by high-resolution ultrasound, and birth registry data were available for 670 children of the Southern California Children’s Health Study. Multivariate regression analyses were performed to investigate the association between birth weight and CIMT, with adjustment for child’s health status and lifestyle, pregnancy information, and parental health.
Results
Mean CIMT was 0.57 mm (SD 0.04). We found a nonlinear association between birth weight and CIMT, with an increase in CIMT of 0.014 mm in the fifth (P value .01) compared with the third birth weight quintile. These associations were robust in subsample analyses in children considered normal-weight by gestational age or in term-born children. No significant association with CIMT was found for the lowest quintile.
Conclusions
Greater birth weight was significantly associated with increased CIMT at age 11 years. No evidence for an impact of lower birth weight was found. The predictive value of childhood CIMT on future cardiovascular outcomes is largely unknown, but strong associations between childhood cardiovascular disease risk factors and adult vascular disease suggest that increased CIMT in childhood may be clinically important.
doi:10.1016/j.jpeds.2012.10.060
PMCID: PMC4030536  PMID: 23260106
19.  Self-Reported Menopausal Symptoms, Coronary Artery Calcification and Carotid Intima-Media Thickness in Recently Menopausal Women Screened for the Kronos Early Estrogen Prevention Study (KEEPS) 
Fertility and sterility  2013;99(5):1385-1391.
Objective
To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis.
Setting
Multi-center, randomized controlled trial.
Patients
Recently menopausal women (n=868) screened for the Kronos Early Estrogen Prevention Study (KEEPS).
Design
Cross sectional analysis.
Interventions
None
Main Outcome Measures
Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum estradiol (E2) levels and measures of atherosclerosis were assessed. Atherosclerosis was quantified using Coronary Artery Calcium (CAC) Agatston scores (n=771) and Carotid Intima-Media Thickness (CIMT). Logistic regression model of menopausal symptoms and E2 was used to predict CAC. Linear regression model of menopausal symptoms and E2 was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, estradiol (E2), CAC, and CIMT were assessed.
Results
In early menopausal women screened for KEEPS, neither E2 nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations (p=0.09) and depression (p=0.07) approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E2 predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness and E2.
Conclusions
Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine if baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease.
doi:10.1016/j.fertnstert.2012.11.053
PMCID: PMC3615128  PMID: 23312232
KEEPS; estrogen; cardiovascular; menopause; CAC; CIMT; palpitations; depression
20.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
Objective
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Conclusions
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
doi:10.1161/ATVBAHA.112.300346
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
22.  Association of subclinical atherosclerosis with lipid levels amongst antiretroviral-treated and untreated HIV-infected women in the Women’s Interagency HIV Study 
Atherosclerosis  2012;225(2):408-411.
Objective
We examined serum lipids in association with carotid artery intima-media thickness (CIMT) in HIV-infected and HIV-uninfected women.
Methods
In 2003–4, among 1827 Women’s Interagency HIV Study participants, we measured CIMT and lipids (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], total cholesterol [TC], non-HDL-c). A subset of 520 treated HIV-infected women had pre-1997 lipid measures. We used multivariable linear regression to examine associations between lipids and CIMT.
Results
In HIV-uninfected women, higher TC, LDL-c and non-HDL-c were associated with increased CIMT. Among HIV-infected women, associations of lipids with CIMT were observed in treated but not untreated women. Among the HIV-infected women treated in 2003–4, CIMT was associated both with lipids measured a decade earlier in infection, and with late lipid measurements.
Conclusion
Among HIV-infected women, hyperlipidemia is most strongly associated with subclinical atherosclerosis in treated women. Among treated women, the association appeared strongest early in the disease course.
doi:10.1016/j.atherosclerosis.2012.09.035
PMCID: PMC3696584  PMID: 23089369
cardiovascular diseases; carotid arteries; HAART; HIV; lipids
23.  Biomarkers of Microbial Translocation and Macrophage Activation: Association With Progression of Subclinical Atherosclerosis in HIV-1 Infection 
The Journal of Infectious Diseases  2012;206(10):1558-1567.
Background. The relationships between soluble CD14 (sCD14), endotoxin (lipopolysaccharide [LPS]), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) infection.
Methods. We retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group [ACTG] 5078), where subjects were enrolled as risk factor–controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)–based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (ΔCIMT).
Results. In multivariate analysis of the HIV-infected subjects, each 1 µg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 µm/y (95% confidence interval, .07–2.98; P = .04) in the ΔCIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 µm/y (95% confidence interval, .18–.81; P = .003) in the ΔCIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ΔCIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1).
Conclusions. Our data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.
doi:10.1093/infdis/jis545
PMCID: PMC3475633  PMID: 23066162
24.  Associations between vascular risk factors, carotid atherosclerosis and cortical volume and thickness in older adults 
Background and Purpose
To investigate whether the Framingham Cardiovascular Risk Profile (FCRP) and carotid artery intima-media thickness (CIMT) are associated with cortical volume and thickness.
Methods
Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3T and 4T MRI at three sites. Freesurfer (v5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of FCRP and CIMT with cortical volume and thickness
Results
152 subjects (82 men) were aged 78 (±7) years old, 94 had a CDR of 0, 58 had a clinical dementia rating (CDR) of 0.5 and the mean mini-mental status examination (MMSE) was 28 ± 2. FCRP score was inversely associated with total gray matter (GM) volume, parietal and temporal GM volume (adjusted p<0.04). FCRP was inversely associated with parietal and total cerebral GM thickness (adjusted p<0.03). CIMT was inversely associated with thickness of parietal GM only (adjusted p=0.04). Including history of myocardial infarction or stroke and radiologic evidence of brain infarction, or apoE genotype did not alter relationships with FCRP or CIMT.
Conclusions
Increased cardiovascular risk was associated with reduced GM volume and thickness in regions also affected by Alzheimer’s disease (AD), independent of infarcts and apoE genotype. These results suggest a “double hit” toward developing dementia when someone with incipient AD also has high cardiovascular risk.
doi:10.1161/STROKEAHA.112.659722
PMCID: PMC3732460  PMID: 22984010
Framingham cardiovascular risk profile; carotid intima media thickness; gray matter; cortical volume; cortical thickness; atrophy
25.  Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults 
Circulation  2012;126(13):1614-1620.
Background
Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.
Methods and results
The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007–2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and socio-demographic characteristics and a 12-hr fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency’s Air Quality System (AQS) database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (± 54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12) O3 exposure was associated with a 7.8 μm (95% CI −0.3, 15.9) or 10.1 μm (95% CI 1.8, 18.5) higher CIMT, respectively. Lifetime exposure to O3 showed similar but non-significant associations. No associations were observed for PM2.5, PM10 or NO2 although adjustment for these pollutants strengthened the childhood O3 associations.
Conclusion
Childhood exposure to O3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
doi:10.1161/CIRCULATIONAHA.112.096164
PMCID: PMC3474843  PMID: 22896588
atherosclerosis; cardiovascular diseases; carotid arteries; epidemiology; pediatrics

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